From structure to systems: high-resolution, quantitative genetic analysis of RNA polymerase II.

RNA polymerase II (RNAPII) lies at the core of dynamic control of gene expression. Using 53 RNAPII point mutants, we generated a point mutant epistatic miniarray profile (pE-MAP) comprising ∼60,000 quantitative genetic interactions in Saccharomyces cerevisiae. This analysis enabled functional assignment of RNAPII subdomains and uncovered connections between individual regions and other protein complexes. Using splicing microarrays and mutants that alter elongation rates in vitro, we found an inverse relationship between RNAPII speed and in vivo splicing efficiency. Furthermore, the pE-MAP classified fast and slow mutants that favor upstream and downstream start site selection, respectively. The striking coordination of polymerization rate with transcription initiation and splicing suggests that transcription rate is tuned to regulate multiple gene expression steps. The pE-MAP approach provides a powerful strategy to understand other multifunctional machines at amino acid resolution.

Re-examine the transfusion transmitted risk of SARS-CoV-2 virus during a major COVID-19 outbreak in 2022.

INTRODUCTION: Although no case of COVID-19 transmission through transfusion has been reported, blood transfusion service (BTS) continues to implement pre-donation and post-donation measures to minimise the risk. In year 2022, when local healthcare system was badly impacted by a major outbreak, it opened an opportunity to re-examine the viraemia risk in these asymptomatic donors. MATERIALS AND METHODS: Records were retrieved from blood donors who reported COVID-19 after donation and follow-up was also made for recipients who received their blood. Blood samples at donation were tested for SARS-CoV-2 viraemia by single-tube nested real-time RT-PCR assay designed to detect most SARS-CoV-2 variants including the prevailing delta and omicron variants. RESULTS: From 1 January to 15 August 2022, the city with 7.4 M inhabitants recorded 1 187 844 COVID-19 positive cases and 125 936 successful blood donations were received. 781 donors reported to the BTS after donation with 701 being COVID-19 related (including close contact and symptoms respiratory tract infection). 525 COVID-19 were positive at the time of call back or follow-up. Of the 701 donations, they were processed into 1480 components with 1073 discarded upon donors' call back. For remaining 407 components, no recipient was found to have adverse event or COVID-19 positive. 510 samples from the above 525 COVID-19 positive donors were available and all tested negative for SARS-CoV-2 RNA. DISCUSSION: With the negative SARS-CoV-2 RNA in blood donation samples and follow up data in transfusion recipients, the risk of transfusion transmitted COVID-19 appears negligible. However, current measures remains important in securing blood safety with ongoing surveillance of their effectiveness.

Aerosol generation with the use of positive pressure ventilation via supraglottic airway devices: an observational study.

The amount of aerosol generation associated with the use of positive pressure ventilation via a supraglottic airway device has not been quantified. We conducted a two-group, two-centre, prospective cohort study in which we recruited 21 low-risk adult patients scheduled for elective surgery under general anaesthesia with second-generation supraglottic airway devices. An optical particle sizer and an isokinetic sampling probe were used to record particle concentrations per second at different size distributions (0.3-10 µm) during use as well as baseline levels during two common activities (conversation and coughing). There was a median (IQR [range]) peak increase of 2.8 (1.5-4.5 [1-28.1]) and 4.1 (2.0-7.1 [1-18.2]) times background concentrations during SAD insertion and removal. Most of the particles generated during supraglottic airway insertion (85.0%) and removal (85.3%) were < 3 µm diameter. Median (IQR [range]) aerosol concentration generated by insertion (1.1 (0.6-5.1 [0.2-22.3]) particles.cm-3 ) and removal (2.1 (0.5-3.0 [0.1-18.9]) particles.cm-3 ) of SADs were significantly lower than those produced during continuous talking (44.5 (28.3-70.5 [2.0-134.5]) particles.cm-3 ) and coughing (141.0 (98.3-202.8 [4.0-296.5]) particles.cm-3 ) (p < 0.001). The aerosol levels produced were similar with the two devices. The proportion of easily inhaled and small particles (<1 µm) produced during insertion (57.5%) and removal (57.5%) was much lower than during talking (99.1%) and coughing (99.6%). These results suggest that the use of supraglottic airway devices in low-risk patients, even with positive pressure ventilation, generates fewer aerosols than speaking and coughing in awake patients.

Moral distress and psychological status among healthcare workers in a newly established paediatric intensive care unit.

INTRODUCTION: Healthcare workers in intensive care units often experience moral distress, depression, and stress-related symptoms. These conditions can lower staff retention and influence the quality of patient care. This study aimed to evaluate the prevalence of moral distress and psychological status among healthcare workers in a newly established paediatric intensive care unit (PICU) in Hong Kong. METHODS: A cross-sectional questionnaire survey was conducted in the PICU of the Hong Kong Children's Hospital; healthcare workers (doctors, nurses and allied health professionals) were invited to participate. The Revised Moral Distress Scale (MDS-R) Paediatric Version and Depression Anxiety and Stress Scale-21 items were used to assess moral distress and psychological status, respectively. Demographic characteristics were examined in relation to moral distress, depression, anxiety, and stress scores to identify risk factors for poor psychological outcomes. Correlations of moral distress with depression, anxiety, and stress were examined. RESULTS: Forty-six healthcare workers completed the survey. The overall median MDS-R moral distress score was 71. Nurses had a significantly higher median moral distress score, compared with doctors and allied health professionals (102 vs 47 vs 20). Nurses also had the highest median anxiety and stress scores (11 and 20, respectively). Moral distress scores were correlated with depression (r=0.445; P=0.002) and anxiety scores (r=0.417; P<0.05). Healthcare workers intending to quit their jobs had significantly higher moral distress scores (P<0.05). CONCLUSION: Among PICU healthcare workers, nurses had the highest level of moral distress. Moral distress was associated with greater depression, anxiety, and intention to quit. Healthcare workers need support and a sustainable working environment to cope with moral distress.

Proton Compton Scattering from Linearly Polarized Gamma Rays.

Differential cross sections for Compton scattering from the proton have been measured at scattering angles of 55°, 90°, and 125° in the laboratory frame using quasimonoenergetic linearly (circularly) polarized photon beams with a weighted mean energy value of 83.4 MeV (81.3 MeV). These measurements were performed at the High Intensity Gamma-Ray Source facility at the Triangle Universities Nuclear Laboratory. The results are compared to previous measurements and are interpreted in the chiral effective field theory framework to extract the electromagnetic dipole polarizabilities of the proton, which gives α_{E1}^{p}=13.8±1.2_{stat}±0.1_{BSR}±0.3_{theo},ß_{M1}^{p}=0.2∓1.2_{stat}±0.1_{BSR}∓0.3_{theo} in units of 10^{-4} fm^{3}.

Peri-operative management of patients with Parkinson's disease.

Patients with Parkinson's disease are at higher risk of peri-operative medical and surgical complications. Multidisciplinary management, early recognition of potential complications, specialised care of medications and intra-operative protection of the vulnerable brain are all important aspects of the peri-operative management of patients with Parkinson's disease. Advances in continuous dopaminergic treatment, development of a peri-operative Parkinson's disease pathway and application of telemedicine are starting to play a role in improving peri-operative care. Management of patients with advanced Parkinson's disease is also evolving, with potential for incorporation of integrated care and changes in the anaesthetic management for deep brain stimulation surgery. There are new methods for localisation of target nuclei and increasing insight on the effects of anaesthetic drugs on microelectrode recordings and clinical outcomes. Parkinson's disease is a progressive disease, but management is improving with better peri-operative care for patients.

Airway management in children with COVID-19.

The novel coronavirus disease (COVID-19) may result in acute respiratory distress syndrome and respiratory failure, necessitating mechanical respiratory support. Healthcare professionals are exposed to a particularly high risk of contracting the virus while providing resuscitation and respiratory support, which may in turn result in grave consequences and even death. Although COVID-19 has been shown to cause milder disease in children, paediatricians and intensivists who provide care for children must be prepared to provide optimal respiratory support without putting themselves or other medical, nursing, and paramedical staff at undue risk. We propose an airway management approach that is especially relevant in the current COVID-19 pandemic and provides instructions for: (1) Elective intubation for respiratory failure; and (2) Emergency intubation during cardiopulmonary resuscitation. To minimise risk, intubation methods must be kept as straightforward as possible and should include the provision of appropriate personal protection and equipment to healthcare workers. We identify two key considerations: that bag-mask ventilation should be avoided if possible and that bacterial and viral filters should be placed in the respiratory circuit. Our novel approach provides a framework for airway management that could benefit paediatric critical care practitioners who provide care for any children with a novel viral illness, with a focus on infection prevention during high-risk airway management procedures.

Covalent and Hydrogen Bonding in Adsorption of Alanine Molecules on Si(111)7×7.

Molecular adsorption bonding configurations and specific interfacial chemistry of alanine on Si(111)7×7 have been determined by combining the results from scanning tunneling microscopy (STM) and X-ray photoelectron spectroscopy (XPS) with ab initio calculations based on the density functional theory (DFT). XPS spectra of the N 1s region show that alanine molecules bind to the 7×7 surface by N-Si covalent bonding, while STM imaging reveals that such N-H dissociative adsorption of alanine occurs on an adjacent Si adatom-restatom pair, with the dehydrogenated alanine moiety and dissociated H atom occupying the Si adatom and restatom sites, respectively. At a sample bias above +2 V, the dehydrogenated alanine appears as a bright round protrusion, slightly off-center from a Si adatom site and leaning toward the opposite Si adatom across the dimer wall. The off-center character can be attributed to an electrostatic attraction between the electron-rich carbonyl O of the dehydrogenated alanine and electron-deficient nearest Si adatom across the dimer wall. Our DFT calculation also shows that the monodentate O-Si bonding configuration resulting from O-H dissociative adsorption is more thermodynamically favorable than the experimentally observed N-Si bonding configuration, suggesting that the interfacial dissociative adsorption reaction is a kinetically controlled rather than a thermodynamically driven process. Alanine molecules in the second adlayer (transitional layer) are found to attach to those in the first adlayer (interfacial layer) by N···HO hydrogen bonding, as supported by the presence of the N 1s feature at 401.0 eV. An alanine molecule H-bonded to a dehydrogenated alanine in the first adlayer has also been observed in STM as a brighter and larger protrusion close to the expected location of the free OH group in the dehydrogenated first-adlayer alanine. No thick zwitterionic alanine film can be obtained at room temperature possibly due to steric constraint caused by the methyl group.

Correction: High-Resolution Phenotypic Landscape of the RNA Polymerase II Trigger Loop.

[This corrects the article DOI: 10.1371/journal.pgen.1006321.].

The fractionation of phosphorus in UK chalk stream surface waters and its relevance to the regulation and management of water quality.

The regulatory management of river water quality requires measurements of phosphorus that are operationally viable and meaningful in terms of insight into its effects. This need is a particular concern in globally rare and ecologically sensitive chalk streams. P data pertaining to rivers are commonly limited to soluble reactive P; other fractions of P may be of concern but are not routinely monitored. This study seeks to establish the nature and extent of non-regulated forms of P in UK chalk streams. Whilst soluble reactive P in two southern English chalk streams was found to comprise the majority of reactive P in surface waters in the majority of samples, 15-20% of the total reactive P was within other size fractions greater than 0.22 µm. The contribution of reactive P to the total P was highly variable. We conclude that, with some adjustments, the established method of regulatory monitoring of P in UK rivers is viable and valuable. In cases where the levels of reactive P are not consistent with ecological status and/or expected outcomes of programmes of measures, we recommend that targeted analysis of non-regulated forms of P is undertaken as a means to guide and focus management interventions.

Transition Strength Measurements to Guide Magic Wavelength Selection in Optically Trapped Molecules.

Optical trapping of molecules with long coherence times is crucial for many protocols in quantum information and metrology. However, the factors that limit the lifetimes of the trapped molecules remain elusive and require improved understanding of the underlying molecular structure. Here we show that measurements of vibronic line strengths in weakly and deeply bound ^{88}Sr_{2} molecules, combined with ab initio calculations, allow for unambiguous identification of vibrational quantum numbers. This, in turn, enables the construction of refined excited potential energy curves, informing the selection of magic wavelengths that facilitate long vibrational coherence. We demonstrate Rabi oscillations between far-separated vibrational states that persist for nearly 100 ms.

Febrile neutropenia and its associated hospitalization in breast cancer patients on docetaxel-containing regimen: A retrospective cohort study on duration of prophylactic GCSF administration.

PURPOSE: To compare febrile neutropenia (FN) incidence and hospitalization among breast cancer patients on docetaxel with no granulocyte colony-stimulating factors (GCSF) primary prophylaxis (PP), 4/5-day PP, or 7-day PP. METHODS: We identified 3916 breast cancer patients using docetaxel-cyclophosphamide (TC), doxorubicin-cyclophosphamide then docetaxel (AC-T), fluorouracil-epirubicin-cyclophosphamide then docetaxel (FEC-T), docetaxel-carboplatin-trastuzumab (TJH), or docetaxel-doxorubicin-cyclophosphamide (TAC) from a hospital pharmacy dispensing database in Hong Kong between 2014 and 2016. Patients were offered GCSF within 5 days since administering docetaxel. Outcomes included FN incidence, time to first hospitalization, hospitalization rate, and duration. RESULTS: In TC regimen, FN incidence (with odds ratio, OR) of patients with no PP, 4/5-day PP, and 7-day PP was 21.69%, 7.95% (OR 0.31, p < 0.001), and 5.33% (OR 0.20, p < 0.001), respectively. In TJH regimen, FN incidence of patients with no PP, 4/5-day PP, and 7-day PP was 38.26%, 8.33% (OR 0.15, p < 0.001), and 8.57% (OR 0.15, p < 0.001), respectively. FN incidence of patients on AC-T regimen with no PP and 4/5-day PP was 20.93% and 6.84%, respectively (OR 0.28, p = 0.005); with FEC-T regimen, the incidence was 9.91% and 4.77%, respectively (OR 0.46, p = 0.035). Only 3.27% FN cases were not hospitalized. Mean (±standard deviation, SD) time to first hospitalization was 8.21 ± 2.44 days. Mean (±SD) duration of hospitalization for patients with no PP, 4/5-day PP, and 7-day PP was 4.66 ± 2.60, 4.37 ± 2.85, and 5.12 ± 2.97 days, respectively. CONCLUSION: GCSF prophylaxis in breast cancer patients on docetaxel could reduce FN incidence and hospitalization. 4/5-day PP demonstrated similar efficacy to 7-day PP with superior saving benefits on healthcare expenditure.

Comparison of carbetocin and oxytocin infusions in reducing the requirement for additional uterotonics or procedures in women at increased risk of postpartum haemorrhage after Caesarean section.

INTRODUCTION: Postpartum haemorrhage is a major cause of maternal mortality and morbidity, commonly due to uterine atony. Prophylactic oxytocin use during Caesarean section is recommended; patients with a high risk of postpartum haemorrhage may require additional uterotonics or procedures. Carbetocin is a long-acting analogue of oxytocin which has shown beneficial results, compared with oxytocin. This study compared the requirement for additional uterotonics or procedures between at-risk women who underwent carbetocin infusion and those who underwent oxytocin infusion. METHODS: This retrospective cohort study included women at increased risk of postpartum haemorrhage after Caesarean section for various indications in a public hospital. Women who received carbetocin infusion and women who received oxytocin infusion were compared, stratified by Caesarean section timing (elective or emergency). The primary outcome was the requirement for additional uterotonic agents or procedures. Secondary outcomes included total blood loss, operating time, rate of postpartum haemorrhage, need for blood transfusion, and need for hysterectomy. RESULTS: Of 1236 women included in the study, 752 received oxytocin first and 484 received carbetocin first. The two groups had comparable blood loss, operating time, rate of postpartum haemorrhage, requirement for additional uterotonics or procedures, need for blood transfusion, and need for hysterectomy. There was a reduction in the requirement for additional uterotonics or procedures, and in the rate of postpartum haemorrhage for women with major placenta praevia or with multiple pregnancies, following receipt of carbetocin first. CONCLUSION: Compared with oxytocin, carbetocin can reduce the requirement for additional uterotonics or procedures in selected high-risk patient groups.

Congenital infections in Hong Kong: beyond TORCH.

Congenital infections refer to a group of perinatal infections that are caused by pathogens transmitted from mother to child during pregnancy (transplacentally) or delivery (peripartum) which may have similar clinical presentations, including rash and ocular findings. TORCH is the acronym that covers these infections (toxoplasmosis, other [syphilis], rubella, cytomegalovirus, herpes simplex virus). Other important causes of intrauterine/perinatal infection include human immunodeficiency virus, varicella-zoster virus, Treponema pallidum, Zika virus, and parvovirus B19. This overview aims to describe various congenital infections beyond TORCH with a Hong Kong perspective. Intrauterine and perinatal infections are a major cause of in utero death and neonatal mortality, and an important contributor to childhood morbidity. A high index of suspicion for congenital infections and awareness of the prominent features of the most common congenital infections can help to facilitate early diagnosis, tailor appropriate diagnostic evaluation, and initiate appropriate early treatment. Intrauterine infections should be suspected in newborns with clinical features including microcephaly, seizures, cataract, hearing loss, congenital heart disease, hepatosplenomegaly, small for gestational age, and/or rash. Primary prevention of maternal infections during pregnancy is key to the prevention of congenital infection, and resources (if available) should focus on public health promotion and pre-marital counselling.

Congenital infections in Hong Kong: an overview of TORCH.

Congenital infections refer to a group of perinatal infections that may have similar clinical presentations, including rash and ocular findings. TORCH is the acronym that covers these infections (toxoplasmosis, other [syphilis], rubella, cytomegalovirus, herpes simplex virus). There are, however, other important causes of intrauterine/perinatal infections, including enteroviruses, varicella zoster virus, Zika virus, and parvovirus B19. Intrauterine and perinatal infections are significant causes of fetal and neonatal mortality and important contributors to childhood morbidity. A high index of suspicion for congenital infections and awareness of the prominent features of the most common congenital infections can help to facilitate early diagnosis, tailor appropriate diagnostic evaluation, and if appropriate, initiate early treatments. In the absence of maternal laboratory results diagnostic of intrauterine infections, congenital infections should be suspected in newborns with certain clinical features or combinations of clinical features, including hydrops fetalis, microcephaly, seizures, cataract, hearing loss, congenital heart disease, hepatosplenomegaly, jaundice, or rash. Primary prevention of maternal infections during pregnancy is the cornerstone of prevention of congenital infection. Available resources should focus on the promotion of public health.

Association between beta-blocker use and obesity in Hong Kong Chinese elders: a post-hoc analysis.

INTRODUCTION: Studies of Caucasian populations have shown that beta-blockers may exacerbate weight gain, a risk factor for many chronic diseases. Still, beta-blockers are the most prescribed antihypertensives in the Chinese population in Hong Kong. We aimed to explore the association between beta-blocker use, hypertension, and weight status of this population. METHODS: A post-hoc analysis regarding body mass index (BMI) and the use of beta-blockers was performed based on the medication profile of community-dwelling older adults. Participants' BMI, hypertension diagnosis, name, dose, frequency, route of administration of beta-blockers, and other drugs that may alter body weight were recorded. RESULTS: Of 1053 Chinese individuals aged ≥65 years (mean age 76.9±7.2 years, 80% female) from 32 elderly centres in Hong Kong, 18% (185/1053) of them consumed beta-blockers. That group also had a significantly larger proportion of obese individuals (45.9% vs 32.1%, P=0.002). After adjusting for other weight-altering drugs, beta-blockers remained a significant predictor of overweight and obesity (P=0.001). As the hypertensive population had significantly higher BMI than the normotensive population (24.3±3.6 vs 22.9±3.5, P<0.001), a sub-analysis on those with hypertension diagnosis confirmed that only the hypertensive population taking atenolol had a significantly larger population of obese individuals (BMI ≥25) compared with those who took metoprolol (58.9% vs 38.5%, P=0.03) and those who did not take any beta-blockers (58.9% vs 38.4%, P=0.007). CONCLUSIONS: Our findings taken together with other guideline reservations cast doubt on whether beta-blockers, particularly atenolol, should be the major drug prescribed to older adults with hypertension.

The relationship between sarcopenia and fragility fracture-a systematic review.

Sarcopenia is a common geriatric syndrome characterized by progressive decrease of muscle mass and function leading to an increased risk of physical disability, poor quality of life, and mortality. Increasing evidence shows that sarcopenia is related with fragility fractures. This systematic review aimed to summarize the following: (1) the prevalence of sarcopenia in patients with fragility fracture and (2) the associated risk factors for fragility fracture in patients with sarcopenia. Literature search was conducted in PubMed and Cochrane databases. Studies with the prevalence of sarcopenia in elderly patients with fragility fracture and associated risk factors in patients with sarcopenia were included. A total of 15 papers were included, with 10 reporting sarcopenia prevalence, and 5 on fracture risk in patients with sarcopenia. The prevalence of sarcopenia after fracture ranged from 12.4 to 95% in males and 18.3 to 64% in females. The prevalence of sarcopenia in elderly patients with fragility fracture was high, especially in men. Two studies showed that sarcopenia was a risk factor for fragility fracture when associated with low bone mineral density (BMD) but only in men. Caution should be taken for male patients with sarcopenia and low BMD, which is related to significantly increased risk of fractures. There is a pressing need for further research on sarcopenia and its risk on fragility fracture to better understand the relationship, pathophysiology, and mechanisms, which may shed light on potential interventions to improve clinical outcomes.

Are we mis-estimating chemotherapy-induced peripheral neuropathy? Analysis of assessment methodologies from a prospective, multinational, longitudinal cohort study of patients receiving neurotoxic chemotherapy.

BACKGROUND: There are inconsistencies in the literature regarding the prevalence and assessment of chemotherapy-induced peripheral neuropathy (CIPN). This study explored CIPN natural history and its characteristics in patients receiving taxane- and platinum-based chemotherapy. PATIENTS AND METHODS: Multi-country multisite prospective longitudinal observational study. Patients were assessed before commencing and three weekly during chemotherapy for up to six cycles, and at 6,9, and 12 months using clinician-based scales (NCI-CTCAE; WHO-CIPN criterion), objective assessments (cotton wool test;10 g monofilament); patient-reported outcome measures (FACT/GOG-Ntx; EORTC-CIPN20), and Nerve Conduction Studies. RESULTS: In total, 343 patients were recruited in the cohort, providing 2399 observations. There was wide variation in CIPN prevalence rates using different assessments (14.2-53.4%). Prevalence of sensory neuropathy (and associated symptom profile) was also different in each type of chemotherapy, with paclitaxel (up to 63%) and oxaliplatin (up to 71.4%) showing the highest CIPN rates in most assessments and a more complex symptom profile. Peak prevalence was around the 6-month assessment (up to 71.4%). Motor neurotoxicity was common, particularly in the docetaxel subgroup (up to 22.1%; detected by NCI-CTCAE). There were relatively moderately-to-low correlations between scales (rs = 0.15,p < 0.05-rs = 0.48 p < 0.001), suggesting that they measure different neurotoxicity aspects from each other. Cumulative chemotherapy dose was not associated with onset and course of CIPN. CONCLUSION: The historical variation reported in CIPN incidence and prevalence is possibly confounded by disagreement between assessment modalities. Clinical practice should consider assessment of motor neuropathy for neurotoxic chemotherapy. Current scales may not be all appropriate to measure CIPN in a valid way, and a combination of scales are needed.

Vibration treatment modulates macrophage polarisation and enhances early inflammatory response in oestrogen-deficient osteoporotic-fracture healing.

Fracture healing is a well-orchestrated and coordinated process and begins with the inflammatory stage involving the infiltration of immune cells and the release of cytokines, including tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10). Low-magnitude high-frequency vibration (LMHFV) stimulation is effective in promoting fracture healing. The study hypothesis was that the innate immune response was impaired in osteoporotic fracture and LMHFV could positively modulate it. 9-month-old ovariectomy (OVX)-induced osteoporotic rats were randomised into sham (SHAM), OVX control (OVX), OVX-vibration (OVX-VT) or OVX vibration plus administration of COX-2 specific non-steroid anti-inflammatory drugs (OVX-VT-NSAID). LMHFV (35 Hz, 0.3 g) was given 20 min/d and 5 d/week to the treatment groups. Healing and innate immune response were evaluated by weekly radiographs, endpoint micro-computed tomography (µCT), enzyme-linked immunosorbent assay (ELISA) and histomorphometry at weeks 1, 2, 4 and 8 post-treatment. Results showed that OVX slightly elevated systemic inflammation but impaired the innate immune response locally at the fracture site, with significantly lower expressions of TNF-α and IL-6 but higher IL-10 expression during the early stage of healing. LMHFV was effective in accelerating the delayed fracture healing in OVX bones by partly restoring the impaired innate immune response at the fracture site, accompanied by promoted progression of macrophage polarisation from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype. In conclusion, vibration treatment could positively modulate the impaired innate immune response and promote macrophage polarisation in osteoporotic-fracture healing.

A metaphyseal fracture rat model for mechanistic studies of osteoporotic bone healing.

Most osteoporotic fractures occur at metaphyseal regions of long bones. The present study proposed a clinically relevant animal model that satisfied: i) induction of osteoporosis, ii) unilateral complete osteotomy at metaphysis, iii) internal fixation. 6 months old female Sprague-Dawley rats (n = 64) were randomly divided into the ovariectomised-metaphyseal osteotomy (OVX, n = 32) and metaphyseal osteotomy (SHAM, n = 32) groups. The metaphyseal-osteotomy model was created with a plate-fixation of the osteotomy and assessed by X-ray, micro-computed tomography, histomorphometry and mechanical testing at weeks 1, 3 and 6. X-ray results showed complete healing of metaphyseal osteotomy at week 6. Histology showed 3 stages of metaphyseal healing. Stage 1 was characterised by fibrous tissue, consisting of disorganised orientation of collagen fibres, and infiltration of immune cells. At stage 2, a transitional zone consisting of maturing fibrous tissue and differentiating mesenchymal cells with early trabecular bone formation and disorganised woven bone were observed. During stage 3, cortical bone ends unified and woven bone underwent transformation to lamellar bone. OVX group healing was significantly delayed when compared to SHAM samples. The study demonstrated that healing of osteoporotic osteotomy at the metaphyseal region was delayed in terms of radiography, histomorphometry and mechanical strength. These quantitative evaluations, along with histological features, may provide key references for future studies. The animal model may provide additional clinical relevance as most osteoporotic fracture in humans occurs at metaphyseal regions.